WO2016127681A1 - Utilisation de complexe de platine tétranucléaire ponté par 4,4'-bipyridine dans la préparation d'un médicament anti-cellules tumorales télomérase négatives - Google Patents

Utilisation de complexe de platine tétranucléaire ponté par 4,4'-bipyridine dans la préparation d'un médicament anti-cellules tumorales télomérase négatives Download PDF

Info

Publication number
WO2016127681A1
WO2016127681A1 PCT/CN2015/094908 CN2015094908W WO2016127681A1 WO 2016127681 A1 WO2016127681 A1 WO 2016127681A1 CN 2015094908 W CN2015094908 W CN 2015094908W WO 2016127681 A1 WO2016127681 A1 WO 2016127681A1
Authority
WO
WIPO (PCT)
Prior art keywords
cells
telomerase
platinum complex
bipyridine
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2015/094908
Other languages
English (en)
Chinese (zh)
Inventor
赵勇
郑小辉
毛宗万
夏立新
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Yat Sen University
Original Assignee
Sun Yat Sen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Yat Sen University filed Critical Sun Yat Sen University
Publication of WO2016127681A1 publication Critical patent/WO2016127681A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table

Definitions

  • the invention belongs to the field of medicine, and particularly relates to the application of 4,4'-bipyridine bridged tetranuclear platinum complex in preparing anti-telomerase negative tumor drugs.
  • Telomere is a special structure at the end of a chromosome in a eukaryotic organism. It consists of repeating units of DNA and proteins bound to it, which maintains the structural and functional integrity of the chromosome. With each division of the cell, the telomeres are shortened a bit. When the telomeres of normal human cells are shortened to a certain extent, the cells will apoptosis and lose the ability to divide and proliferate.
  • telomere length stability Approximately 80% of cancer cells maintain telomere length stability by expressing telomerase, gaining the ability to divide indefinitely; in addition, approximately 20% of cancer cells do not express telomerase (telomerase-negative tumor cells), they pass The alternative pathway mechanism known as ALT (Alternative Lengthening of Telomeres) extends telomeres to maintain telomere length. Since telomerase is not present in normal human tissue cells, it is a specific anti-cancer target.
  • telomerase-negative tumors include: about 20% of human tumor cells; the tumor cells lack (or fail to detect) telomerase activity; the tumor cells extend telomeres using an ALT (Alternative Lengthening of Telomeres) mechanism; Tumor cells are rich in circular telomeric DNA (C-Circle DNA or T-Circle DNA); in most of the tumor cells, there is an observable APB (Associated Promyelocytic leukaemia Body).
  • ALT Alterative Lengthening of Telomeres
  • telomerase-targeting drugs allow tumor cells to activate ALT mechanisms. Therefore, inhibition of ALT is also an intrinsic requirement and ultimate solution for telomerase-targeted cancer therapy.
  • the object of the present invention is to provide a route capable of effectively inhibiting proliferation of telomerase-negative tumor cells in view of the above technical problems.
  • the present invention provides the use of a 4,4'-bipyridine bridged tetranuclear platinum complex of the following formula (I) for the preparation of a medicament for anti-telomerase-negative tumors:
  • the compound of the above formula (I) is known, and the anion is a nitrate (NO 3 - ) ion, which has extremely high water solubility and good thermal stability.
  • the telomerase-negative tumor is an osteosarcoma.
  • the medicament contains a pharmaceutically acceptable carrier or excipient.
  • Figure 1 is a cell proliferation curve.
  • Figure 2 shows the results of ⁇ -galactosidase staining experiments.
  • Figure 3 shows the results of flow cytometry for detecting apoptosis.
  • human osteosarcoma is taken as an example to illustrate the utility of the compound of formula I (4,4'-bipyridine bridged tetranuclear platinum complex) in inhibiting proliferation of telomerase-negative tumor cells, but it should be understood that although The use of human osteosarcoma as an example to illustrate its use for the preparation of a drug against telomerase-negative tumors, but the term "telomerase-negative tumor” cells as used herein refers to the lack (or inability to detect) telomerase activity, Tumor cells expressing telomerase include, but are not limited to, human osteosarcoma, glioma, and the like.
  • the compound of formula I (4,4'-bipyridyl bridged tetranuclear platinum complex) has a significant inhibitory effect on tumor cell proliferation for a variety of telomerase-negative tumor cells, including but not limited to, for example, human osteosarcoma. .
  • Pulmonary fibroblast (MRC-5, normal cell) cell line, human cervical cancer (HeLa, telomerase positive) cell line, human osteosarcoma (U2OS and SAOS2, telomerase negative) cell line were purchased from China National Species Collection ( CTCC).
  • each cell is counted by a cell counter for each passage, and then some cells are re-inoculated, and the seeding density is still 1 ⁇ 10 6 /dish until the total number of cells in the culture dish is ⁇ 1 ⁇ 10 6 can not be inoculated.
  • ⁇ -galactosidase staining experiment a) After the cell culture is terminated, the medium is directly drained, and then washed 3 times with 1 ⁇ PBS; b) a fixing solution is added to the cells, and fixed at room temperature for 15 minutes; c) After discarding the fixative, rinse it again with 1 ⁇ PBS for 5 min each time; d) the specific staining procedure was carried out according to the method provided on the Biyuntian X-gal staining kit; e) adding the staining solution, Incubate overnight at 37 ° C with CO 2 isolation; f) After the end of staining, continue to rinse 3 times with 1 ⁇ PBS, and observe the cells under a 10 ⁇ microscope and photograph.
  • Flow cytometry experiment a) Collect all cells (including floating cells), adherent cells were collected by 0.25% trypsin digestion, centrifuged, and washed twice with 1 ⁇ PBS, discarded. The supernatant, retaining the pellet (cell); b) collecting the cells Fluor 488annexin V and PI for double dyeing, the specific dyeing process according to Alexa The method provided on the 488annexin V/Dead Cell Apoptosis Kit is operated; c) the stained cell suspension is directly tested by flow cytometry, and the experimental data is fitted by FlowJo software.
  • telomerase-negative cells U2OS and SAOS 2.
  • telomerase-negative human osteosarcoma SAOS2 cells showed significant aging after treatment with the compound (Compound 4 of formula I, 4'-bipyridyl bridged tetranuclear platinum complex).
  • phosphatidylserine In normal cells, phosphatidylserine (PS) is only distributed in the inner side of the lipid bilayer of the cell membrane, but in the early stage of apoptosis The phosphatidylserine (PS) on the cell membrane is turned from the inside to the outside of the lipid membrane, so it is possible to determine whether the cell is in the early stage of apoptosis by detecting the presence of PS on the extracellular surface.
  • Annexin V has a high affinity for PS and can be used to determine the number of apoptotic cells.
  • Propidium Iodide is a nucleic acid dye that does not pass through the intact cell membrane of normal cells or early apoptotic cells, but for advanced cells in apoptosis, PI can pass through the cell membrane and stain the nucleus. .
  • Annexin V By matching Annexin V to PI, cells at different stages of apoptosis can be identified.
  • the lower left quadrant shows live cells
  • the lower right quadrant is the early apoptotic cell
  • the upper left quadrant is the metaphase apoptotic cell
  • the upper right quadrant is the late apoptotic cell.
  • the compound 4,4'-bipyridine bridged tetranuclear platinum complex of the formula I can effectively inhibit the proliferation of telomerase-negative tumor cells and inhibit tumor growth, and can be used for preparing an effective anti-telomerase-negative tumor. drug.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une utilisation d'un complexe de platine tétranucléaire ponté par 4,4'-bipyridine dans la préparation d'un médicament anti-cellules tumorales télomérase négatives, la prolifération de cellules tumorales télomérase négatives pouvant être ainsi inhibée de façon efficace.
PCT/CN2015/094908 2015-02-09 2015-11-18 Utilisation de complexe de platine tétranucléaire ponté par 4,4'-bipyridine dans la préparation d'un médicament anti-cellules tumorales télomérase négatives Ceased WO2016127681A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510069157.4 2015-02-09
CN201510069157.4A CN104693244B (zh) 2015-02-09 2015-02-09 4,4’‑联吡啶桥联四核铂配合物在制备抗端粒酶阴性肿瘤药物中的应用

Publications (1)

Publication Number Publication Date
WO2016127681A1 true WO2016127681A1 (fr) 2016-08-18

Family

ID=53340834

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/094908 Ceased WO2016127681A1 (fr) 2015-02-09 2015-11-18 Utilisation de complexe de platine tétranucléaire ponté par 4,4'-bipyridine dans la préparation d'un médicament anti-cellules tumorales télomérase négatives

Country Status (2)

Country Link
CN (1) CN104693244B (fr)
WO (1) WO2016127681A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115160376A (zh) * 2022-07-13 2022-10-11 南京师范大学 一种肉桂酸修饰的环金属铱（iii）配合物及其合成方法和应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108440602B (zh) * 2018-04-17 2020-06-05 深圳大学 四核铱配合物及其制备方法与应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012155559A1 (fr) * 2011-05-17 2012-11-22 中山大学 Complexe de platine organique à quatre noyaux hybridés et son procédé de préparation ainsi que son utilisation dans la fabrication de médicaments anti-tumoraux

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050113324A1 (en) * 2003-01-15 2005-05-26 Bondarev Igor E. Modulation of line-1 reverse transcriptase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012155559A1 (fr) * 2011-05-17 2012-11-22 中山大学 Complexe de platine organique à quatre noyaux hybridés et son procédé de préparation ainsi que son utilisation dans la fabrication de médicaments anti-tumoraux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XIAOHUI ZHENG ET AL., PT (II) SQUARES AS SELECTIVE AND EFFECTIVE HUMAN TELOMERIC G-QUADRUPLEX BINDERS AND POTENTIAL CANCER THERAPEUTIES DALTON TRANSACTIONS, 31 December 2012 (2012-12-31), pages 11807 - 11812 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115160376A (zh) * 2022-07-13 2022-10-11 南京师范大学 一种肉桂酸修饰的环金属铱（iii）配合物及其合成方法和应用
CN115160376B (zh) * 2022-07-13 2023-11-21 南京师范大学 一种肉桂酸修饰的环金属铱（iii）配合物及其合成方法和应用

Also Published As

Publication number Publication date
CN104693244B (zh) 2017-10-20
CN104693244A (zh) 2015-06-10

Similar Documents

Publication Publication Date Title
Jiang et al. TPX2 regulates tumor growth in human cervical carcinoma cells
Wu et al. LINC00963 promotes hepatocellular carcinoma progression by activating PI3K/AKT pathway.
WO2016062287A1 (fr) Application du médicament cellcept pour la préparation d'une composition pharmaceutique inhibant le cancer
WO2021134512A1 (fr) Nouvelle fonction et nouvelle utilisation du peptide antimicrobien de crabe cryptoïde appelé scyréprocine
Geng et al. ERK5 positively regulates cigarette smoke-induced urocystic epithelial-mesenchymal transition in SV‑40 immortalized human urothelial cells
CN108277279B (zh) 一种lncRNA在诊断和/或治疗乳腺癌中的应用
WO2016127681A1 (fr) Utilisation de complexe de platine tétranucléaire ponté par 4,4'-bipyridine dans la préparation d'un médicament anti-cellules tumorales télomérase négatives
Zhou et al. Cordyceps militaris fraction inhibits the invasion and metastasis of lung cancer cells through the protein kinase B/glycogen synthase kinase 3β/β-catenin signaling pathway
CN104174012A (zh) Otud3蛋白在制备抑制肿瘤生长的产品中的应用
CN107537027A (zh) Tnfsf15蛋白在制备治疗黑色素瘤药物中的用途
Kiseleva et al. The effect of fotemustine on human glioblastoma cell lines
WO2019091183A1 (fr) Utilisations de yd1701 dans la préparation de médicaments pour le traitement de tumeurs à expression élevée d'aldh1a3
Meng et al. Arsenic trioxide promotes mitochondrial DNA mutation and cell apoptosis in primary APL cells and NB4 cell line
CN108186641B (zh) Gsk2193874在制备抗胶质瘤的药物中的应用
CN109908147B (zh) 苯乙烯基环己烯丙二腈衍生物在制备抗肺癌药物中的应用
CN107184585B (zh) Hc-067047在制备抗胶质瘤的药物中的应用
Cai et al. Sox3 silencing inhibits metastasis and growth of esophageal squamous cell carcinoma cell via down-regulating GSK-3β
Celebre et al. Anaplastic meningioma with extensive single-cell infiltration: a potential role for epithelial-mesenchymal transformation in the progression of a meningothelial tumour?
CN106860450B (zh) 毛钩藤碱的应用
CN114832105A (zh) 一种C7orf50基因或蛋白的抑制剂的用途
Liu et al. CXC chemokine-7 inhibits growth and migration of oral tongue squamous cell carcinoma cells, mediated by the epithelial-mesenchymal transition signaling pathway
CN105497916B (zh) 小分子非编码RNAmiR-125b在制备用于治疗肿瘤包绕型血管类型肝癌的药物中的应用
CN107007601A (zh) Af38469在制备抗胶质瘤的药物或保健品中的应用
CN110592021A (zh) 一种肾癌舒尼替尼耐药细胞系、构建方法及其应用
CN103432593B (zh) 一种用于预防或治疗食管癌的药物组合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15881830

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15881830

Country of ref document: EP

Kind code of ref document: A1